Curation DM2 CNBP

Haplotype analysis of 71 families with genetically confirmed DM2; all affected individuals were diagnosed with DM and tested positive for the CNBP/ZNF9 CCTG expansion.

DM2 alleles showed uninterrupted expansion of the CCTG portion of the intron 1 repeat tract (75–~11,000 repeats; mean ~5,000), whereas sequenced normal alleles were interrupted and controls showed no expansion.

Linkage analysis across 17 European-origin PROMM/PDM/DM2 kindreds gave a peak multipoint LOD score of 19.521 at D3S3584; all affected individuals had the CNBP/ZNF9 CCTG expansion.

Drosophila DM2-106 model expressing noncoding (CCUG)106 repeats recapitulated DM2-like RNA foci, MBNL-dependent mis-splicing, retinal/eye disruption, and apoptosis.

In DM2-106 fly muscle, expanded CCUG repeats caused aberrant Fhos exon 24 inclusion (>70% vs ~30% in controls) and altered INSR, TNNT2, and Tnnt3 spliceosensor reporters.

Expanded (CCUG)106 transcripts formed predominantly nuclear RNA foci in fly muscle and retinal cells and sequestered MBNL proteins.

Expression of DM2-106 in Drosophila retina disrupted photoreceptor, cone, and pigment cell organization and induced apoptosis in developing eye imaginal discs.

PKR-I treatment reduced/disrupted CCUG RNA foci and apoptosis in DM2-106 eye imaginal discs; the paper notes adult eye morphology was not rescued after larval feeding.

In DM2 skeletal muscle, the mutant CNBP/ZNF9 allele showed retention of intron 1 sequences and aberrant intron 3-retaining transcripts, consistent with impaired splicing and reduced mRNA/protein levels.

Patient skeletal muscle biopsies and myoblast cultures from genetically confirmed DM2 cases showed reduced CNBP/ZNF9 mRNA/protein, altered localization, and aberrant splicing compared with normal and DM1 controls.